PROJECT SUMMARY:! Each year millions of patients undergo cardiovascular evaluation for stable angina, which is typically caused by flow-limiting stenosis of the epicardial coronary arteries. However, up to ~40% of men and ~60% of women with stable angina referred for coronary angiography do not have obstructive coronary artery disease (CAD). Even in patients with moderate to severe ischemia by stress testing, 21% have non-obstructive CAD, defined as normal coronary arteries or <50% diameter stenosis in all epicardial coronary vessels at angiography. In the absence of obstructive epicardial CAD, ischemia is often mediated by coronary microvascular disease. Coronary microvascular disease is present in 25-40% of patients with ischemia and non-obstructive CAD and a diagnosis of microvascular disease by invasive testing is associated with increased risks of death, myocardial infarction, and heart failure. Non-invasive surrogate measures of coronary microvascular disease in non- coronary vascular beds have not been identified. Despite its prevalence and adverse clinical implications, the pathogenesis of coronary microvascular disease is unknown. Coronary microvascular disease may reflect a systemic microvascular abnormality. Impairments in microvascular function due to endothelial dysfunction, abnormal vasodilatory responses to stress, and microvascular obstruction are hypothesized. Each of these processes may be in part mediated by platelet interactions with the vascular endothelium. Activated platelets are known to induce endothelial dysfunction directly and through interactions with inflammatory cells. Increased platelet aggregation has been reported in stable patients with ischemia and non-obstructive CAD in comparison to both patients with obstructive CAD and healthy controls. If platelets do mediate coronary microvascular disease, then modulation of platelet activity could be therapeutic. We propose to evaluate measures of platelet activity as a potential mechanism of coronary microvascular disease in a cohort of men and women with stable ischemia and non-obstructive CAD undergoing invasive measurements of microvascular function (Aim 1). We also plan to identify non-invasive correlates of coronary microvascular disease in non-coronary microvascular beds that can be characterized in vivo (Aim 2). This may facilitate diagnosis of microvascular disease in future clinical trials. This proposal will advance the training of the PI as a clinical and translational investigator in ischemic heart disease through a curriculum of structured mentorship, didactic coursework, participation in research-related conferences, and protected time for research. The proposal addresses critical question 4.CQ.05 in NHLBI strategic visioning, will yield novel insights into the physiology and mechanisms of coronary microvascular disease, and will provide a foundation for future investigations into microvascular disease diagnosis, pathogenesis, and treatment.